Pharmaceutical compositions of a thiazolidinedione derivative and their use as antidiabetics

ABSTRACT

A polymorphic form of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt (the “Polymorph”) characterised in that it: (i) provides an infra red spectrum containing peaks at 1360, 1326, 1241, 714 and 669 cm −1 ; and/or (ii) provides a Raman spectrum containing peaks at 1581, 768, 670, 271 and 226 cm −1 ; and/or (iii) provides a solid-state nuclear magnetic resonance spectrum containing peaks at chemical shifts substantially as set out in Table I; and/or (iv) provides an X-ray powder diffraction (XRPD) pattern containing peaks substantially as set out in Table II; a process for preparing such a compound, a pharmaceutical composition containing such a compound and the use of such a compound in medicine.

[0001] This invention relates to a novel pharmaceutical, to a processfor the preparation of the pharmaceutical and to the use of thepharmaceutical in medicine.

[0002] International Patent Application, Publication Number WO94/05659discloses certain thiazolidinedione derivatives having hypoglycaemic andhypolipidaemic activity including5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt (hereinafter also referred to as “Compound (I)”).

[0003] International Patent Applications, Publication NumbersWO99/31093, WO99/31094 and WO99/31095 each disclose distinct hydrates ofCompound (I).

[0004] It has now been discovered that Compound (I) exists in a novelpolymorphic form which is particularly suitable for bulk preparation andhandling. The novel form can be prepared by an efficient, economic andreproducible process particularly suited to large-scale preparation.

[0005] The novel polymorphic form (‘the Polymorph’) also has usefulpharmaceutical properties and in particular it is indicated to be usefulfor the treatment and/or prophylaxis of diabetes mellitus, conditionsassociated with diabetes mellitus and certain complications thereof.

[0006] Accordingly, the present invention provides a polymorphic form of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt characterised in that it:

[0007] (i) provides an infra red spectrum containing peaks at 1360,1326, 1241, 714 and 669 cm⁻¹; and/or

[0008] (ii) provides a Raman spectrum containing peaks at 1581, 768,670, 271 and 226 cm⁻¹; and/or

[0009] (iii) provides a solid-state nuclear magnetic resonance spectrumcontaining peaks at chemical shifts substantially as set out in Table I;and/or

[0010] (iv) provides an X-ray powder diffraction (XRPD) patterncontaining peaks substantially as set out in Table II.

[0011] In one favoured aspect, the Polymorph provides an infraredspectrum substantially in accordance with FIG. I.

[0012] In one favoured aspect, the Polymorph provides a Raman spectrumsubstantially in accordance with FIG. II.

[0013] In one favoured aspect, the Polymorph provides a solid-statenuclear magnetic resonance spectrum substantially in accordance withFIG. III.

[0014] In one favoured aspect, the Polymorph provides an X-ray powderdiffraction (XRPD) pattern substantially in accordance with FIG. IV.

[0015] The present invention encompasses the Polymorph isolated in pureform or when admixed with other materials, for example the known formsof Compound I or any other material.

[0016] Thus in one aspect there is provided the Polymorph in isolatedform.

[0017] In a further aspect there is provided the Polymorph in pure form.

[0018] In yet a further aspect there is provided the Polymorph incrystalline form.

[0019] The invention also provides a process for preparing thePolymorph, characterised in that a slurry of Compound (I) in aqueousethanol containing up to about 2.5% w/v water, preferably aqueousdenatured ethanol containing up to about 2.5% w/v water, for example2.5% w/v water, is heated, suitably to a temperature in the range offrom 35° C. and 60° C., such as 40° C. to 50° C., for example to 45° C.,for an extended period of time, for example 65 hours, after which timethe Polymorph is recovered from the denatured ethanol. Optionally, thereaction mixture is seeded with the Polymorph.

[0020] In a further process of the invention, Compound (I) is admixedwith denatured ethanol, heated to an elevated temperature, preferably atemperature in the range of from 35° C. and 60° C., such as 40° C. to50° C., for example from 45° to 47° C., over an extended period of time,for example 65 hours, after which time the Polymorph is recovered fromthe solvent. Optionally, the reaction mixture is seeded with Polymorph.

[0021] In a further process a solution of Compound (I) in denaturedethanol containing up to 2.5% w/v water, for example 0.8 to 2.5% w/vwater, at 55° C. is seeded with the Polymorph then cooled to atemperature in the range of from 20° C. to 25° C. to provide thePolymorph. The Polymorph is then recovered from the denatured ethanol.

[0022] The solution of Compound (I) in the denatured ethanol isconveniently prepared by dissolving Compound (I) in the required amountof denatured ethanol at an elevated temperature, for example 60° C. Inour hands this latter process is also effectively carried out usingCompound (I) containing up to 25% w/w of the hydrate disclosed inWO99/31093 mentioned above

[0023] Conveniently the Polymorph is recovered from the reactionsolvent, such as denatured ethanol, by filtration and subsequent drying,preferably at an elevated temperature, for example 45° C.

[0024] In a further aspect the present invention also provides a processfor preparing Compound (I) (also for convenience referred to as the“Original Polymorph”) from the Polymorph of the invention, which processcomprises first preparing a solution of the Polymorph in a mixture(100:1 v/v) of absolute ethanol and methanol, at an elevatedtemperature, suitably in the range of from 60° C. to 75° C. for exampleat 68° C., and then allowing the solution to cool to ambienttemperature, for example 20-25° C., thereby allowing the OriginalPolymorph to crystallise.

[0025] In a preferred form of the said process to prepare the OriginalPolymorph, the solution of the Polymorph in the absoluteethanol/methanol mixture is filtered, usually once complete dissolutionof the Polymorph is attained and the resulting solution is reheated toan elevated temperature, for example to 65° C., which solution is thenallowed to cool to ambient temperature, for example 20 to 25° C.

[0026] In the above mentioned processes for preparing the OriginalPolymorph the solution may be seeded with the Original Polymorph butthis is not essential.

[0027] Compound (I) is prepared according to known procedures, such asthose disclosed in WO94/05659. The disclosures of WO94/05659 areincorporated herein by reference.

[0028] For the avoidance of doubt the term “Compound (I)” as used hereinrefers to the form of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt as disclosed an characterised in International PatentApplication, Publication Number WO94/05659. When used herein “denaturedethanol” means ethanol containing small amounts of methanol, usually upto 5% v/v of methanol, such as from 0.9% v/v to 5% v/v of methanol, forexample ethanol containing 4% v/v of methanol.

[0029] When used herein the term ‘prophylaxis of conditions associatedwith diabetes mellitus’ includes the treatment of conditions such asinsulin resistance, impaired glucose tolerance, hyperinsulinaemia andgestational diabetes.

[0030] Diabetes mellitus preferably means Type II diabetes mellitus.

[0031] Conditions associated with diabetes include hyperglycaemia andinsulin resistance and obesity. Further conditions associated withdiabetes include hypertension, cardiovascular disease, especiallyatherosclerosis, certain eating disorders, in particular the regulationof appetite and food intake in subjects suffering from disordersassociated with under-eating, such as anorexia nervosa, and disordersassociated with over-eating, such as obesity and anorexia bulimia.Additional conditions associated with diabetes include polycysticovarian syndrome and steroid induced insulin resistance.

[0032] The complications of conditions associated with diabetes mellitusencompassed herein includes renal disease, especially renal diseaseassociated with the development of Type II diabetes including diabeticnephropathy, glomerulonephritis, glomerular sclerosis, nephroticsyndrome, hypertensive nephrosclerosis and end stage renal disease.

[0033] As mentioned above the compound of the invention has usefultherapeutic properties: The present invention accordingly the Polymorphfor use as an active therapeutic substance.

[0034] More particularly, the present invention provides the Polymorphfor use in the treatment and/or prophylaxis of diabetes mellitus,conditions associated with diabetes mellitus and certain complicationsthereof.

[0035] The Polymorph may be administered per se or, preferably, as apharmaceutical composition also comprising a pharmaceutically acceptablecarrier. The formulation of the Polymorph and dosages thereof aregenerally as disclosed for Compound (I) in International PatentApplication, Publication Numbers WO94/05659 and WO98/55122.

[0036] Accordingly, the present invention also provides a pharmaceuticalcomposition comprising the Polymorph and a pharmaceutically acceptablecarrier therefor.

[0037] The Polymorph is normally administered in unit dosage form.

[0038] The active compound may be administered by any suitable route butusually by the oral or parenteral routes. For such use, the compoundwill normally be employed in the form of a pharmaceutical composition inassociation with a pharmaceutical carrier, diluent and/or excipient,although the exact form of the composition will naturally depend on themode of administration.

[0039] Compositions are prepared by admixture and are suitably adaptedfor oral, parenteral or topical administration, and as such may be inthe form of tablets, capsules, oral liquid preparations, powders,granules, lozenges, pastilles, reconstitutable powders, injectable andinfusable solutions or suspensions, suppositories and transdermaldevices. Orally administrable compositions are preferred, in particularshaped oral compositions, since they are more convenient for generaluse.

[0040] Tablets and capsules for oral administration are usuallypresented in a unit dose, and contain conventional excipients such asbinding agents, fillers, diluents, tabletting agents, lubricants,disintegrants, colourants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art.

[0041] Suitable fillers for use include cellulose, mannitol, lactose andother similar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

[0042] Solid oral compositions may be prepared by conventional methodsof blending, filling, tabletting or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations are,of course, conventional in the art.

[0043] Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs,or may be presented as a dry product for reconstitution with water orother suitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

[0044] For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the active compound in a vehicle and filtersterilising before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

[0045] Parenteral suspensions are prepared in substantially the samemanner except that the active compound is suspended in the vehicleinstead of being dissolved and sterilised by exposure to ethylene oxidebefore suspending in the sterile vehicle. Advantageously, a surfactantor wetting agent is included in the composition to facilitate uniformdistribution of the active compound.

[0046] In addition such compositions may contain further active agentssuch as anti-hypertensive agents and diuretics.

[0047] In addition, the Polymorph may be used in combination with otherantidiabetic agents such as insulin secretagogues, for examplesulphonylureas, biguanides, such as metformin, alpha glucosidaseinhibitors, such as acarbose, beta agonists, and insulin such as thosedisclosed in WO98/57649, WO98/57634, WO98/57635 or WO98/57636. The otherantidiabetic agents, the amounts thereof and methods of administrationare as described in the above mentioned publications. The formulation ofthe Polymorph and dosages thereof in said combinations are generally asdisclosed for Compound (I) in the above mentioned publications. As iscommon practice, the compositions will usually be accompanied by writtenor printed directions for use in the medical treatment concerned.

[0048] As used herein the term ‘pharmaceutically acceptable’ embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term ‘pharmaceutically acceptable salt’ embraces aveterinarily acceptable salt.

[0049] The present invention further provides a method for the treatmentand/or prophylaxis of diabetes mellitus, conditions associated withdiabetes mellitus and certain complications thereof, in a human ornon-human mammal which comprises administering an effective, non-toxic,amount of the Polymorph to a human or non-human mammal in need thereof.Conveniently, the active ingredient may be administered as apharmaceutical composition herein before defined, and this forms aparticular aspect of the present invention.

[0050] In the treatment and/or prophylaxis of diabetes mellitus,conditions associated with diabetes mellitus and certain complicationsthereof the Polymorph may be taken in doses, such as those describedabove.

[0051] Similar dosage regimens are suitable for the treatment and/orprophylaxis of non-human mammals.

[0052] In a further aspect the present invention provides the use of thePolymorph for the manufacture of a medicament for the treatment and/orprophylaxis of diabetes mellitus, conditions associated with diabetesmellitus and certain complications thereof.

[0053] No adverse toxicological effects are indicated in the abovementioned treatments for the compounds of the invention.

[0054] The following examples illustrate the invention but do not limitit in any way.

EXAMPLES Example 1

[0055] A slurry of Compound (I) (3.0 g, prepared as per WO94/05659 indenatured ethanol (30.5 ml, water content 2.5% w/v) ) was heated at 45°C. for 65 hours. The product was filtered at 45° C. and dried at 50° C.in vacuo to give the Polymorph (1.55 g).

Example2

[0056] To a mixture of absolute ethanol (30 ml, water <0.1 % w/v) andmethanol (1.2 ml) was added Compound (I) (2.00 g). The resultingsuspension was heated to 45-7° C. and maintained at this temperature for65 h. The solid was isolated at 45° C. and dried at 50° C. in vacuo togive 0.83 g (41%) of Polymorph.

Example 3

[0057] Compound (I) (6.0 g, containing approximately 25% w/w of thehydrate disclosed in WO99/31093) was heated at 60° C. in denaturedethanol (60 ml, water content 0.8% w/v) until complete dissolution wasobtained. The resultant solution was cooled to 55° C., seeded with thetitle compound (0.06 g), then cooled to 20-25° C. The product wasfiltered, washed with denatured ethanol (10 ml) and dried at 50° C. invacuo to give the Polymorph (4.8 g, 80%).

Example 4 Conversion of the Polymorph to Compound (I) (the OriginalPolymorph)

[0058] The Polymorph (4.0 g) was heated to 68° C. in a mixture ofabsolute ethanol (40 ml) and methanol (0.4 ml) until completedissolution was obtained. The resultant solution was filtered, re-heatedto 65° C., and then cooled to 20-25° C. The product was filtered, washedwith absolute ethanol (8 ml) and dried at 50° C. in vacuo to giveCompound (I) as disclosed in WO94/05659 (3.32 g, 83%).

CHARACTERISING DATA

[0059] The following characterising data were generated for Thepolymorph:

[0060] A Water Content

[0061] This was determined as 0.08% w/w using a Karl Fischer apparatus.

[0062] B Infrared

[0063] The infrared absorption spectrum of a mineral oil dispersion ofthe Polymorph was obtained using a Nicolet 710 FT-IR spectrometer at 2cm⁻¹ resolution. Data were digitised at 1 cm⁻¹ intervals. The spectrumobtained is shown in FIG. I. Peak positions are as follows: 2720, 1750,1703, 1640, 1618, 1610, 1573, 1541, 1529, 1513, 1412, 1400, 1360, 1326,1309, 1300, 1265, 1241, 1213, 1183, 1162, 1112, 1096, 1080, 1068, 1033,1014, 989, 972, 933, 902, 866, 843, 832, 812, 774, 741, 734, 729, 669,660, 636, 613, 605, 577, 558, 540, 527, 515, 508 and 473 cm⁻¹.

[0064] C Raman

[0065] The Raman spectrum of the Polymorph was recorded through a glassvial using a Perkin Elmer 2000R spectrometer at 4 cm⁻¹ resolution and isshown in FIG. II (X-axis shows Intensity, Y-axis shows Raman shift cm⁻¹,1800-200 cm⁻¹). Excitation was achieved using a Nd:YAG laser (1064 nm)with a power output of 400 mW. Peak positions are as follows: 1749,1706, 1683, 1611, 1581, 1546, 1511, 1468, 1445, 1435, 1388, 1361, 1327,1301, 1269, 1250, 1229, 1210, 1179, 1149, 1103, 1056, 1036, 1024, 1005,989, 920, 843, 827, 800, 782, 768, 744, 722, 670, 637, 605, 560, 541,512, 473, 429, 408, 397, 347, 322, 298, 271 and 226 cm⁻¹.

[0066] D NMR

[0067] The 90.56 MHz ¹³C CP-MAS NMR spectrum for the Polymorph is shownin FIG. III. Chemical shifts are tabulated in Table I. Data wererecorded at ambient temperature and 10 kHz spinning frequency on aBruker AMX360 spectrometer, with 1.6 ms cross polarization, and arepetition time of 15 s. Chemical shifts were externally referenced tothe carboxylate signal of a glycine test sample at 176.4 ppm relative totetramethylsilane, and are regarded as accurate to within +/−0.5 ppm.Peaks were not assigned. TABLE I ¹³C Chemical Shifts of the Polymorph.Chemical Shift (ppm) 42.2 112.3 131.5 146.5 172.4 50.7 113.9 134.1 151.4177.4 55.9 118.8 138.7 158.7 62.7 129.8 140.5 170.3

[0068] E X-Ray Powder Diffraction (XRPD)

[0069] The XRPD pattern of the Polymorph is shown below in FIG. IV and asummary of the XRPD angles and calculated lattice spacingscharacteristic of the Polymorph is given in Table II.

[0070] A PW1710 X-ray powder diffractometer (Cu X-ray source) was usedto generate the powder pattern using the following acquisitionconditions: Tube anode: Cu Generator tension: 40 kV Generator current:30 mA Start angle:  3.5° 2θ End angle:  35.0° 2θ Step size: 0.020° 2θTime per step: 2.3 s

[0071] TABLE II X-Ray Powder Diffraction Angles and Calculated LatticeSpacings Characteristic of the Polymorph. Diffraction Angle LatticeSpacing (°2θ) (Angstroms) 8.9 9.90 12.0 7.35 14.0 6.32 15.4 5.73 15.95.55 16.8 5.26 17.4 5.08 18.1 4.89 19.2 4.60 19.6 4.52 20.0 4.44 20.34.37 20.8 4.27 21.2 4.18 22.3 3.97 23.7 3.80 24.3 3.75 25.1 3.54 25.83.44 26.7 3.33 27.2 3.27 28.7 3.10 29.6 3.01 30.6 2.92 31.6 2.83 32.22.78 33.3 2.69

1. A polymorphic form of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt (the “Polymorph”) characterised in that it: (i)provides an infra red spectrum containing peaks at 1360, 1326, 1241, 714and 669 cm⁻¹; and/or (ii) provides a Raman spectrum containing peaks at1581, 768, 670, 271 and 226 cm⁻¹; and/or (iii) provides a solid-statenuclear magnetic resonance spectrum containing peaks at chemical shiftssubstantially as set out in Table I; and/or (iv) provides an X-raypowder diffraction (XRPD) pattern containing peaks substantially as setout in Table II.
 2. A Polymorph according to claim 1, which provides aninfra red spectrum substantially in accordance with FIG. I.
 3. APolymorph according to claim 1 or claim 2, which provides a Ramanspectrum substantially in accordance with FIG. II.
 4. A Polymorphaccording to any on of claims 1 to 3, which provides a solid-statenuclear magnetic resonance spectrum substantially in accordance withFIG. III.
 5. A Polymorph according to any one of claims 1 to 4, whichprovides an X-ray powder diffraction (XRPD) pattern substantially inaccordance with FIG. IV.
 6. A Polymorph according to any one of claims 1to 5, in isolated form.
 7. A Polymorph according to any one of claims 1to 6, in pure form.
 8. A Polymorph according to any one of claims 1 to7, in crystalline form.
 9. A process for preparing a Polymorph accordingto claim 1, characterised in that: (a) a slurry of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt (hereinafter also referred to as “Compound (I)” or the“Original Polymorph”) in aqueous ethanol containing up to about 2.5% w/vwater, is heated for an extended period of time; after which time thePolymorph is recovered from the denatured ethanol; or (b) Compound (I)is admixed with denatured ethanol, heated to an elevated temperature,over an extended period of time, after which time the Polymorph isrecovered from the solvent; or (c) Compound (I) in denatured ethanolcontaining up to 2.5% w/v water at 55° C. is seeded with the Polymorphthen cooled to a temperature in the range of from 20° C. to 25° C. toprovide the Polymorph; the Polymorph is then recovered from the solvent.10. A pharmaceutical composition comprising an effective, non-toxicamount of a Polymorph according to claim 1 and a pharmaceuticallyacceptable carrier therefor.
 11. A Polymorph according to claim 1, foruse as an active therapeutic substance.
 12. A Polymorph according toclaim 1, for use in the treatment and/or prophylaxis of diabetesmellitus, conditions associated with diabetes mellitus and certaincomplications thereof.
 13. The use of Polymorph for the manufacture of amedicament for the treatment and/or prophylaxis of diabetes mellitus,conditions associated with diabetes mellitus and certain complicationsthereof.
 14. A method for the treatment and/or prophylaxis of diabetesmellitus, conditions associated with diabetes mellitus and certaincomplications thereof, in a human or non-human mammal which comprisesadministering an effective, non-toxic, amount of Polymorph to a human ornon-human mammal in need thereof.